T reg Cells in Myocarditis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. However, both types of virus are extremely common and not everyone experiencing an enterovirus/adenovirus infection will develop myocarditis. Both host and viral factors determine viral pathogenicity. We have developed a murine model of coxsackievirus B3 myocarditis where the H3 variant of the virus induces severe myocarditis while a mutant of the H3 virus, designated H310A1, is non-myocarditic. The H3 and H310A1 variants differ by a single non-conserved amino acid mutation in the VP2 capsid protein. The H310A1 variant stimulates CD4+ T regulatory (T reg) cells which actively suppress the pathogenic immunity induced by H3 virus infection. The T reg cells are CD4+CD25+FoxP3+. A major difference in H3 and H310A1 infections is that H3 virus is a potent inducer of systemic TNFa while H310A1 infection induces little of this cytokine. Studies by others and us have shown that exogenous administration of recombinant TNFa exacerbates myocarditis susceptibility in normally resistant mice. Thus, giving TNFa to H310A1 infected mice restores myocarditis susceptibility and greatly reduces TGF¿ expression by T reg cells. Since TGF¿ mediates immunosuppression at least by TH3 cells, we hypothesize that TNFa modulates TH3 cell activation or function. This is surprising since TNFa has been reported to promote the Tr1 type of T reg cell. It is possible that TNFa may have different effects on induction of distinct types of T reg cells, promoting some and inhibiting others. In the current model, we believe that TNFa might abrogate T reg cells through induction of CD1d, a non-classical MHC class I protein, and activation of T cells expressing the V?4 T cell receptor. V?4+ cells in viral myocarditis are CDId-restricted and adoptive transfer of activated V?4+ cells into H310A1 infected mice restores myocarditis susceptibility. In this proposal, we wish to: 1. Determine whether T reg cells are Tr1, Th3 or natural T reg cells which means they should suppress adaptive immunity through IL-10, TGF¿ or cell-cell contact; 2. Determine the relative roles of infection (TLR), TNFa, CD1d and V?4+ T cells in generation or abrogation of T reg cells; and 3. Determine whether the T reg cells are antigen specific (virus), cardiovascular specific (autoimmunity), or non-antigen specific.